Purine Salvage Pathway in Mycobacterium tuberculosis

Abstract

Millions of deaths worldwide are caused by the aetiological agent of tuberculosis, Mycobacterium tuberculosis. The increasing prevalence of this disease, the emergence of drug-resistant strains, and the devastating effect of human immunodeficiency virus coinfection have led to an urgent need for the development of new and more efficient antimycobacterial drugs. The modern approach to the development of new chemical compounds against complex diseases, especially the neglected endemic ones, such as tuberculosis, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a specific target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, and (iii) the development of compounds with selective toxicity. The present review describes the enzymes of the purine salvage pathway in M. tuberculosis as attractive targets for the development of new antimycobacterial agents. Enzyme kinetics and structural data have been included to provide a thorough knowledge on which to base the search for compounds with biological activity. We have focused on the mycobacterial homologues of this pathway as potential targets for the development of new antitubercular agents.

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis

“…However, guanine was unable to rescue Mtb from VCC234718 toxicity at a drug concentration of 128 μM, suggesting that this compound has a secondary target (or targets) in Mtb . In contrast, and as expected from what is known about purine salvage in Mtb , 40 xanthine supplementation had no effect on VCC234718 toxicity over the same concentration range (data not shown). Likewise, neither adenine nor guanosine supplementation was able to rescue Mtb from VCC234718 toxicity (data not shown).…”

“…39,40 We thus hypothesized that guanine supplementation might alleviate the toxicity caused by VCC234718 treatment or GuaB2 depletion in Mtb by enabling an alternate route to GMP production via the action of hypoxanthine-guanine phosphoribosyl transferase, Hpt (Rv3624c; hypoxanthine-guanine phosphoribosyl transferase). 40,41 Indeed, guanine supplementation showed clear dose-dependent alleviation of VCC234718 toxicity in Mtb , raising the MIC 90 of VCC234718 from 2 to >64 μM at a guanine concentration of 200 μM (Figure 4B). However, guanine was unable to rescue Mtb from VCC234718 toxicity at a drug concentration of 128 μM, suggesting that this compound has a secondary target (or targets) in Mtb .…”

Structural Analyses of a Purine Biosynthetic Enzyme from Mycobacterium tuberculosis Reveal a Novel Bound Nucleotide

“…Two types of pathways exist in most organisms for the production of these compounds as follows: the de novo biosynthetic pathway, in which nucleotides are synthesized from 5Ј-phosphoribosylpyrophosphate (PRPP) 4 in a multistep series of reactions (1); and salvage pathways, in which nucleotides are retrieved after the breakdown of nucleic acids or coenzymes (2,3). These two alternatives may be relatively more or less important in a given organism or in response to different cellular requirements.…”

Kinetic mechanism and energetics of binding of phosphoryl group acceptors to Mycobacterium tuberculosis cytidine monophosphate kinase

“…Nucleoside monophosphate (NMP) kinases play pivotal roles in both de novo synthesis and salvage pathway of DNA and RNA precursors [9,10]. Bacterial cytidine 5 0 -monophosphate (CMP) kinase (CMK), which is part of pyrimidine nucleotide interconversion pathways, catalyzes the c-phosphoryl group transfer from, usually, adenosine-5 0 -triphosphate (ATP) to either CMP or 2 0 -deoxy-CMP (dCMP).…”